Role of Aldosterone and Adiponectin in Inter-Tissue Communication in Diastolic He

醛固酮和脂联素在舒张期肝组织间通讯中的作用

基本信息

批准号：
8841816
负责人：
Flora Sam
金额：
$ 40.31万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841816
关键词：
Accounting Address Adenovirus Vector Adipocytes Adipose tissue Aldosterone Angiotensin II Angiotensins Animal Model Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Attenuated Autophagocytosis Biometry Calcium Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Communication Cells Clinical Coculture Techniques Collagen Communication Development Diastolic heart failure Disease Progression Dose EFRAC Extracellular Matrix Fatty acid glycerol esters Functional disorder Health Heart Diseases Heart failure Human Hypertension Incidence Individual Inflammatory Investigation Left Left Ventricular Hypertrophy Link Matrix Metalloproteinases Measurement Measures Mediating Modeling Molecular Biology Morbidity - disease rate Mus Obesity Pathogenesis Pathologic Patients Pharmaceutical Preparations Phosphorylation Plasma Proteins Play Prevalence Proteins Relative (related person)Research Personnel Resistant Hypertension Risk Factors Role Signal Transduction Specialist Symptoms Systolic heart failure Testing Tissues Transgenic Mice Ventricular Work abdominal fat adipokines adiponectin blood pressure regulation cytokine experience molecular phenotype mortality mouse model overexpression research study stem subcutaneous translational study

项目摘要

DESCRIPTION (provided by applicant): Diastolic heart failure (HF), also known as "heart failure-preserved-ejection fraction", accounts for up to 50% of all HF presentations, but unlike systolic HF, therapies remain ineffective despite increasing morbidity and mortality. This stems, in part, from a lack of mechanistic understanding about diastolic HF. Hypertension is the major cause of diastolic HF and the prevalence of diastolic HF is projected to increase as the incidence of hypertension rises. Obese individuals also have a high incidence of poorly controlled blood pressure and diastolic HF. This raises the possibility that factors secreted by fa may play a role in hypertension-related diastolic HF. Although a causal link exists between aldosterone and arterial hypertension, increasing evidence demonstrates a link between aldosterone and obesity with evidence that adipocytes, in addition to secreting adiponectin (APN), may release secreted factors that stimulate aldosterone release independent of angiotensin-II. APN, an adipose-derived plasma protein, exerts anti-inflammatory and anti-hypertrophic effects by modulating phosphorylation signals in cardiovascular cells and is implicated in the development of hypertension and systolic HF. APN levels are decreased in obesity and hypertension, but elevated in systolic HF, also known as "heart failure-reduced-ejection fraction". Conversely aldosterone is increased in obesity, hypertension and in HF. Recently our lab showed that hypoadiponectinemia in hypertension-induced diastolic HF exacerbates left ventricular hypertrophy, diastolic dysfunction and diastolic HF. We seek to examine the contribution of APN to the relative increase in aldosterone in diastolic HF. The broad objective of this proposal is that dysregulation between aldosterone and APN contributes to the pathogenesis of diastolic HF and adverse cardiac remodeling. To our knowledge this conceptual model has not been tested nor hypothesized. We will test the hypothesis that an alteration in APN levels facilitates an increase in aldosterone increasing the propensity to diastolic HF and diastolic dysfunction. To address this hypothesis we will test the following aims: Aim 1) to investigate if dysregulation of APN levels are associated with alterations in aldosterone levels in human diastolic HF. Hypothesis 1. Aldosterone and APN levels are elevated in stable diastolic HF patients and are associated with left ventricular (LV) diastolic dysfunction measurements. Hypothesis 2. Changes in aldosterone and APN levels (between acutely, decompensated and stable, ambulatory diastolic HF) are associated with disease progression (as determined by echocardiographic derived measures of LV diastolic dysfunction) in diastolic HF. Aim 2) To determine if APN ameliorates the transition from hypertension to diastolic dysfunction and diastolic HF in a mouse model of diastolic HF and dysfunction. Aim 3) To investigate the role of autophagy in diastolic dysfunction in cardiac myocytes and the signaling mechanisms involved in cell-to-cell communication between cardiac myocytes and adipocytes in diastolic HF.

描述（由申请人提供）：舒张期心力衰竭（HF），也称为“心力衰竭保留的换位分数”，占所有HF表现的50％，但与收缩期HF不同，尽管发病率和死亡率增加，疗法仍然无效。这部分原因是对舒张期HF缺乏机械理解。高血压是舒张期HF的主要原因，舒张期HF的患病率预计会随着高血压的发生率增加。肥胖个体的血压和舒张压HF的发生率也很高。这增加了FA分泌的因素可能在与高血压相关的舒张压HF中发挥作用的可能性。尽管醛固酮与动脉高血压之间存在因果关系，但越来越多的证据表明，醛固酮与肥胖之间的联系与证据表明，除分泌脂联素（APN）外，脂肪细胞还可能释放出刺激醛固酮释放的分泌因素，这些因素独立于血管素素-III。 APN是一种脂肪衍生的血浆蛋白，通过调节心血管细胞中的磷酸化信号来发挥抗炎和抗营养性作用，并与高血压和收缩期HF的发展有关。肥胖症和高血压的APN水平降低，但收缩的HF（也称为“减少心力衰竭的预测分数”）升高。相反，醛固酮在肥胖，高血压和HF中增加。最近，我们的实验室表明，高血压诱导的舒张性HF患者左心室肥大，舒张功能障碍和舒张期HF中的低脂肪核酸血症。我们试图研究APN对舒张体HF中醛固酮相对增加的贡献。该提案的广泛目的是醛固酮和APN之间的失调有助于舒张期HF和不良心脏重塑的发病机理。据我们所知，这种概念模型尚未得到测试或假设。我们将检验以下假设：APN水平的改变有助于醛固酮增加，从而增加了舒张期HF和舒张功能障碍的倾向。为了解决这一假设，我们将测试以下目的：目的1）研究APN水平的失调是否与人舒张性HF中醛固酮水平的改变有关。假设1。稳定的舒张性HF患者的醛固酮和APN水平升高，与左心室（LV）舒张功能障碍测量相关。假设2。醛固酮和APN水平的变化（急性，代偿性和稳定，卧床可舒张性HF）与疾病进展（通过超声心动图衍生的LV舒张功能障碍的测量值确定）在舒张期HF中有关。目标2）确定APN是否可以改善舒张期HF和功能障碍的小鼠模型中从高血压到舒张功能障碍和舒张期HF的过渡。目标3）研究自噬在心肌细胞中舒张功能障碍中的作用以及心肌细胞和脂肪细胞之间细胞对细胞通信的信号传导机制在舒张性HF中。